Respirable particulates in occupational and environmental aerosols deposit on mucus and respiratory membranes of the lung. Efficient clearance of these deposited particulates is necessary for normal lung function. Knowledge of normal clearance rate, route and retention sites is necessary for understanding lung dosimetry and dysfunction when challenged by excessive numbers of particulates, cytotoxic or radioactive particles or infectious organisms. Animal studies have indicated that increasing particle burdens in the lung depress rate and alter routes of clearance. In man, a number of studies suggest particle excess in the lung can lead to the fibrotic lung and other diseases. We have determined normal rate and routes of clearance in a large animal, the sheep whose lung size and anatomy is similar to man and can provide lung dosimetry in regard to sites of particle deposition, retention and particle burden concentrations which may be directly applicable to man. The present study will examine the effect of increasing inhaled particle loads on subsequent clearance via our established sheep experimental methodology. In these loading studies, two particle sizes will be used: 2.85 & 0.52 um (count median diameter) and these sizes will be inhaled individually and mixed to deliver low and high lung particle burdens. In separate groups of sheep under high and low particle loads, we will examine 1) the rate and routes of particle clearance from the lung in the intact sheep by serial gamma camera imaging and serial fecal and urine collections and, at autopsy, by total lung lavage and radiolabel well counting of other organs and regional lymph nodes, and 2) inhaled particle to cell interactions, by comparing cells and particles collected serially from chronic sheep tracheal stomae with serial bronchoalveolar lavage for the numbers of contained particles in macrophages and free particles, as well as differential particle uptake by the cells, 3) macrophage function and activation, on the basis of their cytotoxic capacity, procoagulant and fibrinolytic activity, release of oxygen metabolites, and their Fcy receptor levels, and 4) the microscopic and EM location of particle retention sites in the lung. Such studies should elucidate the major mechanisms whereby high deposited particle loads damage lung defenses, impair particle clearance and alter clearance routes.